A major challenge of demyelinating diseases, particularly Multiple Sclerosis (MS), is the progression to a condition of chronic demyelination and incomplete remyelination. The reasons for the incomplete remyelination are not known. Largely disregarded is the fact that the human CNS contains significant amounts of latent viruses, most of which are members of the herpes virus family. Infection with human herpesviruses 6A (HHV6) in humans results in almost all cases in viral latency, a state where the virus does not produce a fully infectious virion. Establishment of latency of HHV6 involves formation of a viral nuclear episome, integration into the human genome and expression of the viral protein U94. In ~1% of the human population this occurs in the germline resulting in a single copy of the viral genome in every nucleated cell (ciHHV) and while it has been reported that ciHHV6 carriers display some mild developmental delays during childhood, the impact of ciHHV6 on the susceptibly or response to demyelination is not known. However, an emerging literature shows strong associations between the presence of HHV6 DNA and MS lesions, and a significant subset of chronic MS patients shows serological responses consistent with latent infections. Moreover, our preliminary data provide evidence for (i) chromosomal integration, latency, and expression of U94 after infection of hOPCs, (ii) impaired migration of U94 expressing OPC in vitro and after transplantation and (iii) molecular changes, like downregulation of intreginV5, in U94 expressing OPCs. No available animal models have exploited the presence of this ?CNS virome? and its potential to impair remyelination in the context of myelin damage. To address this paucity, we focus on the role of latent HHV6, a dominant component of the ?CNS virome?. While the species specificity of HHV6 precludes the generation of animal models via primary viral infection, the expression of the latency-associated viral protein U94 offers the opportunity to model at least some aspects of HHV6 latency in an animal model. We propose to generate an inducible U94 transgenic mouse models that mimics aspects of HHV6 latency and test the hypothesis that expression of the latency associated viral protein U94 in oligodendrocyte progenitor cells (OPCs) plays a role in the progression of demyelinating disease. The ability to migrate to the site of myelin damage and differentiate into mature myelinating oligodendrocytes is a critical component of the repair process, but the quantitation of impaired de and re-myelination using transplantation approaches are limited. The proposed new animal model will allow us to determine the impact of U94 on myelination during development and the impact on demyelination and remyelination after injury.